Improved Outcomes With Adjuvant Chemoendocrine vs Endocrine Therapy in Premenopausal Women With Node-Positive Breast Cancer and Recurrence Score ≤ 25

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In an interim analysis of a phase III trial (RxPONDER) reported in The New England Journal of Medicine, Kevin Kalinsky, MD, MS, of Winship Cancer Institute, and colleagues found that the addition of adjuvant chemotherapy to endocrine therapy improved invasive disease–free survival among premenopausal women—but not postmenopausal women—with hormone receptor (HR)-positive, HER2-negative, node-positive breast cancer and a 21-gene assay recurrence score ≤ 25.1 The recurrence score was prognostic for outcomes in all patients, but no association of chemotherapy benefit with increasing recurrence score was observed.

Kevin Kalinsky, MD, MS

Kevin Kalinsky, MD, MS

The investigators stated: “The recurrence score based on the 21-gene breast cancer assay has been clinically useful in predicting a chemotherapy benefit in HR-positive, HER2-negative axillary lymph node–negative breast cancer. In women with positive lymph node disease, the role of the recurrence score with respect to predicting a benefit of adjuvant chemotherapy is unclear.”

In the open-label trial, 5,018 eligible women with 1 to 3 positive axillary lymph nodes and a recurrence score of ≤ 25 were randomly assigned between February 2011 and September 2017 to receive chemoendocrine therapy (n = 2,511) or endocrine therapy alone (n = 2,507). Patients had to be eligible for a chemotherapy regimen containing a taxane, an anthracycline, or both. Randomization was stratified by recurrence score (0–13 or 14–25), premenopausal or postmenopausal status, and type of axillary surgery (sentinel node biopsy or axillary lymph node dissection). The primary objective was to determine the effect of chemotherapy on invasive disease–free survival and whether the effect was influenced by the recurrence score.

Invasive Disease–Free Survival

At the prespecified third interim analysis, median follow-up was 5.3 years. At this analysis, the independent data and safety monitoring committee and National Cancer Institute recommended reporting the data since the effect of chemotherapy on invasive disease–free survival differed markedly according to menopausal status, with the effect not being expected to change with accrual of additional events.

Among all patients, invasive disease–free survival at 5 years was 92.2% in the chemoendocrine group vs 91.0% in the endocrine group (P = .10). No significant interaction was found between chemotherapy benefit and recurrence score categories of 0 to 13 and 14 to 25 (P = .89) or type of axillary surgery (P = .13). After adjustment for chemotherapy benefit and menopausal status, the recurrence score was independently prognostic for invasive disease–free survival among all patients (hazard ratio [HR] per unit increase in recurrence score = 1.05, 95% confidence interval [CI] = 1.04–1.07, P < .001).

The effect of chemotherapy on invasive disease–free survival differed significantly according to menopausal status (P = .008). Invasive disease–free survival at 5 years was 91.3% in the chemoendocrine group vs 91.9% in the endocrine group (HR = 1.02, 95% CI = 0.82–1.26, P = .89) among postmenopausal women and 93.9% vs 89.0% (HR = 0.60, 95% CI = 0.43–0.83, P = .002) among premenopausal women. Among postmenopausal women, no benefit of chemoendocrine therapy was observed in any subgroups examined (age, tumor grade, tumor size, number of positive nodes, type of axillary surgery, and recurrence score of 0–13 or 14–25), whereas all subgroups exhibited benefit of chemoendocrine therapy among premenopausal women.

Impact of Recurrence Score

After adjustment for age, treatment group, number of positive nodes, histologic grade, and tumor size, the recurrence score was significantly prognostic for invasive disease–free survival in both postmenopausal women (HR per unit increase = 1.05, 95% CI = 1.03–1.07, P < .001) and premenopausal women (HR per unit increase = 1.06, 95% CI = 1.02–1.09, P = .001).

In post hoc analysis of invasive disease–free survival by recurrence score groupings among postmenopausal women, no significant differences in outcome by treatment were observed for scores ≤ 10 (HR for chemoendocrine vs endocrine therapy = 0.72, 95% CI = 0.44–1.18), 11 to 15 (HR = 1.30, 95% CI = 0.88–1.92), 16 to 20 (HR = 0.91, 95% CI 0.57–1.43), or 21 to 25 (HR = 1.13, 95% CI = 0.75–1.70). Among premenopausal women, a significant difference favoring chemoendocrine therapy was observed among patients with a recurrence score of 16 to 20 (HR = 0.57, 95% CI = 0.35–0.94), but no significant differences were observed according to scores of ≤ 10 (HR = 0.47, 95% CI = 0.18–1.20), 11 to 15 (HR = 0.68, 95% CI = 0.33–1.37), or 21 to 25 (HR = 0.63, 95% CI = 0.30–1.31).

Among postmenopausal women, overall hazard ratios for chemoendocrine vs endocrine therapy were 1.01 (95% CI = 0.77–1.33) for a recurrence score of 14 to 25 and 1.01 (95% CI = 0.71–1.44) for a recurrence score of 0 to 13. Among premenopausal women, hazard ratios were 0.63 (95% CI = 0.43–0.91) and 0.49 (95% CI = 0.24–0.99), respectively.


  • Chemoendocrine therapy improved invasive disease–free survival vs endocrine therapy in premenopausal but not postmenopausal women with node-positive breast cancer.
  • The recurrence score was prognostic for outcomes but not associated with a benefit of addition of chemotherapy to endocrine therapy.

Distant Relapse–Free Survival

For the chemoendocrine group vs the endocrine group, distant relapse–free survival at 5 years was 94.9% vs 93.9% (HR = 0.88, 95% CI = 0.71–1.09, P = .25) among all patients, 94.4% vs 94.4% (HR = 1.05, 95% CI = 0.81–1.37, P = .70) among postmenopausal women, and 96.1% vs 92.8% (HR = 0.58, 95% CI = 0.39–0.87, P = .009) among premenopausal women.

The investigators concluded: “Among premenopausal women with one to three positive lymph nodes and a recurrence score of 25 or lower, those who received chemoendocrine therapy had longer invasive disease–free survival and distant relapse–free survival than those who received endocrine-only therapy, whereas postmenopausal women with similar characteristics did not benefit from adjuvant chemotherapy.… We confirmed the prognostic value of a recurrence score between 0 and 25 in both premenopausal and postmenopausal participants with N1 breast cancer; however, the hypothesis that the relative chemotherapy benefit increases as the recurrence score value increases was not supported in either population.” 

DISCLOSURE: The study was funded by the National Cancer Institute, Susan G. Komen for the Cure Research Program, Hope Foundation for Cancer Research, Breast Cancer Research Foundation, and Genomic Health. Dr. Kalinsky has served as a consultant to 4D Pharma, AstraZeneca, Cyclacel, Daiichi Sankyo, Eisai, Eli Lilly, Merck, Novartis, OncoSec, Pfizer, and Seattle Genetics; has received institutional research funding from Acetylon, Amgen, Calithera, CytomX, Eli Lilly, Genentech, Immunomedics, Novartis, Pfizer, Seattle Genetics, and Zentalis; has served on steering committees for Ambryx, AstraZeneca, Genentech, and Immunomedics; and his spouse has been employed by Array BioPharma and Grail. 


1. Kalinsky K, Barlow WE, Gralow JR, et al: 21-gene assay to inform chemotherapy benefit in node-positive breast cancer. N Engl J Med 385:2336-2347, 2021.


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